Isaacs' manager, Copeland Forbes, said the singer died Monday at his London home. Isaacs had been diagnosed with lung cancer a year ago, but continued performing until weeks before his death.
His wife Linda said Isaacs was "well-loved by everyone, his fans and his family, and he worked really hard to make sure he delivered the music they loved and enjoyed."
Born in a Kingston, Jamaica slum in 1951, Isaacs began recording in his teens, and went on to produce scores of albums .
With his sinuous baritone and romantic songs, Isaacs became a leading proponent of the mellow "Lovers Rock" style of reggae. He hit his stride in the mid-1970s with ballads like "Love is Overdue" and "All I Have Is Love."
Later that decade he teamed up with the Jamaican production duo of Sly Dunbar and Robbie Shakespeare for several hit songs including "Soon Forward" and "What A Feeling."
"Gregory's voice and writing ability was wicked. He was one of those soulful singers you could sit and listen to for hours," Dunbar said Monday.
Isaacs was best known internationally for the title song from his 1982 album "Night Nurse," a club favorite which later became a hit for Simply Red.
His career was stalled by a cocaine habit that landed him in jail on several occasions. Isaacs said ruefully in 2007 that he'd gone to "Cocaine High School ... the greatest college ever, but the most expensive school fee ever paid."
Drug abuse took a toll on his voice but he kept making music, releasing a well-received final album, "Brand New Me," in 2008.
Suggs, lead singer of reggae-influenced British band Madness, said the dapper, fedora-sporting Isaacs was "a great reggae artist and also one of the most sartorially elegant stars on the world stage."